In this application the PI proposes to continue studies on topologically constrained oligonucleotides which are designed to bind to RNA or DNA. These oligonucleotides are capable of forming triple-stranded complexes with targeted nucleic acids and include circular oligonucleotides, stem- loop oligonucleotides, purine hairpin oligonucleotides, and cross-linked and bicyclic oligonucleotides. The specific aims of the proposal include: (1) Exploration of novel approaches to targeting structured nucleic acids; (2) Optimization of modifications for enhancing RNA-binding properties; (3) Evaluation of new synthetic approaches to topologically modified oligonucleotides; and (4) Collaborative testing of these new molecular strategies in HIV-infected cells. The long term objectives of the studies are to optimize the performance of synthetic oligonucleotides and to test them in applications directly related to HIV-1 infection. This includes both medical diagnostic and potentially therapeutic applications.